ENDOTOXIN, NITRIC OXIDE SYNTHASE AND VASCULAR REACTIVITY.
SCOTT, J. A., M. MACHOUN, AND D. G. McCORMACK.
A. C. Burton Vascular Biology Laboratory, Departments of Medicine,
Pharmacology and Toxicology, University of Western Ontario, London, Ontario,
Canada
APStracts 2:0383A, 1995.
We tested the hypothesis that selective inhibition of the inducible form of
nitric oxide (NO) synthase with aminoguanidine would prevent the loss of
vascular contractility following exposure to endotoxin (LPS). Aortic rings
were dissected from Sprague-Dawley rats, suspended in organ baths containing
Krebs' solution, and tested for vascular reactivity. Vessels incubated with
LPS (1 _g/ml) for five hours exhibited a significant decrease in the maximal
contractile response to phenylephrine. Aminoguanidine (100 _M) restored the
maximal contractile response of LPS-treated vessels to the level of the
control vessels. Aminoguanidine was approximately 250 fold less potent than-
NAME in inhibiting the constitutive NO synthase in vascular tissue to produce
an EC®MDSD¯50®MDNM¯ contraction in phenylephrine (10 nM) precontracted
vessels. NO synthase activity was determined in vascular tissue incubated with
and without LPS. Vessels incubated with LPS exhibited marked increase in the
levels of inducible NO synthase activity compared to control vessels. This
increase was restored to control levels when tissue homogenates were incubated
with aminoguanidine. We conclude that aminoguanidine is a selective
concentration- dependent inhibitor of the inducible form of NO synthase and
may be a useful probe to evaluate the role of inducible NO synthase in the
abnormal vascular contractility characteristic of endotoxemia and sepsis.
Received 28 November 1994; accepted in final form 1 September 1995.
APS Manuscript Number A1201-4.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.